Brennan F X, Albeck D S, Paylor R
Medical Research, VA Medical Center, Philadelphia, PA 19104, USA.
Genes Brain Behav. 2006 Aug;5(6):467-71. doi: 10.1111/j.1601-183X.2005.00183.x.
Fragile X syndrome (FXS) is the most common form of inherited mental retardation (MR). FXS is typically caused by a mutation of the Fmr1 gene (Verkerk et al. 1991, Cell 65, 905-914). To better understand the role of Fmr1 and its gene product fragile X mental-retardation protein (FMRP) in central nervous system function, researchers have turned to the use of animal model systems to generate an Fmr1 knockout (KO) mouse that is deficient in FMRP (Bakker et al. 1994, Cell 78, 23-33). Unfortunately, a number of studies have found no consistent, robust learning and memory impairment in the Fmr1 KO mice. We conducted a study to assess the performance of Fmr1 KO and wildtype (WT) animals in a leverpress escape/avoidance paradigm. Fmr1 KO and WT littermates were studied in four daily 1-h sessions. The Fmr1 KO mice performed fewer avoidance and total responses than WT mice. The KO animals were not simply deficient in avoidance, but a within-factor ANOVA revealed that they did not acquire the leverpress response to any appreciable degree. Observation during the sessions indicated that the Fmr1 KO animals clearly responded to the shock, eliminating an obvious sensory explanation for the deficit. The fact that other studies have found that the KO mice displayed increased exploratory and locomotor activity compared with WT controls argues against a motoric deficit. Future studies will attempt to delineate the nature of the behavioral deficit as well as attempt to rescue the response with glutamatergic or dopaminergic agents.
脆性X综合征（FXS）是遗传性智力迟钝（MR）最常见的形式。FXS通常由Fmr1基因突变引起（Verkerk等人，1991年，《细胞》65卷，905 - 914页）。为了更好地理解Fmr1及其基因产物脆性X智力迟钝蛋白（FMRP）在中枢神经系统功能中的作用，研究人员已转向使用动物模型系统来培育缺乏FMRP的Fmr1基因敲除（KO）小鼠（Bakker等人，1994年，《细胞》78卷，23 - 33页）。不幸的是，许多研究发现Fmr1基因敲除小鼠在学习和记忆方面没有一致的、明显的损伤。我们进行了一项研究，以评估Fmr1基因敲除小鼠和野生型（WT）动物在杠杆按压逃避/回避范式中的表现。对Fmr1基因敲除小鼠和野生型同窝小鼠进行了为期四天、每天1小时的研究。Fmr1基因敲除小鼠的回避反应和总反应次数均少于野生型小鼠。基因敲除动物不仅仅是在回避方面存在缺陷，单因素方差分析显示它们在任何明显程度上都没有获得杠杆按压反应。实验过程中的观察表明，Fmr1基因敲除动物对电击有明显反应，排除了缺陷的明显感觉方面的解释。其他研究发现基因敲除小鼠与野生型对照相比表现出探索和运动活动增加，这一事实排除了运动缺陷的可能性。未来的研究将试图确定行为缺陷的本质，并尝试用谷氨酸能或多巴胺能药物挽救这种反应。
